As many cases of type 2 diabetes (T2D) are likely to remain undiagnosed, better tools for early detection of high‐risk individuals are needed to prevent or postpone the disease. We investigated the value of the doubly weighted genetic risk score (dwGRS) for the prediction of incident T2D in the Lifelines and Estonian Biobank (EstBB) cohorts. The dwGRS uses an additional weight for each single nucleotide polymorphism in the risk score, to correct for “Winner's curse” bias in the effect size estimates. The traditional (single‐weighted genetic risk score; swGRS) and dwGRS were calculated for participants in Lifelines (n = 12,018) and EstBB (n = 34,129). The dwGRS was found to have stronger association with incident T2D (hazard ratio [HR] = 1.26 [95% confidence interval: 1.10–1.43] and HR = 1.35 [1.28–1.42]) compared to the swGRS (HR = 1.21 [1.07–1.38] and HR = 1.25 [1.19–1.32]) in Lifelines and EstBB, respectively. Comparing the 5‐year predicted risks from the models with and without the dwGRS, the continuous net reclassification index was 0.140 (0.034–0.243; p = .009 Lifelines), and 0.257 (0.194–0.319; p < 2 × 10⁻¹⁶ EstBB). The dwGRS provided incremental value to the T2D prediction model with established phenotypic predictors. It clearly distinguished the risk groups for incident T2D in both biobanks thereby showing its clinical relevance.

中文翻译：

---

在Lifelines和Estonian Biobank队列中验证双加权遗传风险评分以预测2型糖尿病。

由于许多2型糖尿病（T2D）病例可能仍未得到诊断，因此需要更好的工具来及早发现高风险个体，以预防或推迟该疾病。我们调查了双重加权遗传风险评分（dwGRS）在生命线和爱沙尼亚生物银行（EstBB）队列中预测T2D事件的价值。dwGRS对风险评分中的每个单核苷酸多态性使用额外的权重，以纠正效应量估计中的“赢家的诅咒”偏见。计算了生命线（n  = 12,018）和EstBB（n的参与者）的传统（单加权遗传风险评分； swGRS）和dwGRS。 = 34,129）。与swGRS（HR = 1.21 [1.07–1.0]）相比，发现dwGRS与事件T2D关联更强（危险比[HR] = 1.26 [95％置信区间：1.10–1.43]和HR = 1.35 [1.28–1.42]）。在生命线和EstBB中分别为1.38]和HR = 1.25 [1.19–1.32]。比较使用和不使用dwGRS的模型的5年预测风险，连续净重分类指数分别为0.140（0.034-0.243; p  = .009生命线）和0.257（0.194-0.319; p  <2×10 ^-16 EstBB ）。dwGRS通过已建立的表型预测因子为T2D预测模型提供了增量值。它清楚地区分了两个生物库中发生T2D的风险类别，从而显示了其临床相关性。